Age and Nutritional Status by Mini-Nutritional Assessment (MNA) can discriminate Alzheimer’s Disease Severity

— Investigate the risk factors associated with Clinical Dementia Rating (CDR) in patients with Alzheimer's disease (AD). Cross-sectional study with 43 elderly people with AD. Parameters assessing nutritional status (anthropometry and mini-nutritional assessment-MNA), neurocognitive assessment and Clinical Dementia Rating (CDR) were investigated. For the investigation of AD severity risk factors, statistical analysis was performed using logistic regression models. The level of significance adopted was 5%. No statistically significant difference in the relationship between the parameters of anthropometry nutritional assessment and the CDR score were found. In the final regression model; only MNA


INTRODUCTION
Alzheimer's disease (AD) is a neurodegenerative disease prevalent in the elderly. It is well known that incorporation of lifestyle changes, as well as physical and recreational activities, diet and cognitive activity, among others, are important to prevent the disease 1 . Evidence of preventive interventions 1 could encourage or contribute to the treatment of this population. Recent studies 2,3 have indicated the importance of some nutrients which shortage is associated with the development of AD. These nutrients contribute to the synthesis of neurotransmitters, modulation in epigenetic mechanisms and with antioxidants 2. In elderly patients with subjective cognitive decline, clinically relevant findings have been associated with the quality of the diet 3 .
Regarding the nutritional status of patients with AD, a study 4 showed a high prevalence of malnutrition or risk of malnutrition detected by the mini nutritional assessment (MAN), in patients with different severity, also associated with reduced functional status. Another recent study 5 which investigated the association between nutritional status and clinical and cognitive aspects of patients with AD, showed significant progressive impairment of nutritional and cognitive indicators related to disease progression. In a crosssectional study 6 , assessing the nutritional status and body composition and mild cognitive impairment in patients with AD, the MAN score was significantly lower, compared to healthy elderly controls. Dementia was also considered an independent predictor of malnutrition risk, when compared to cognitively intact individuals 7 .
Recently, a prospective multicenter study 8 investigating the nutritional status in AD and its influence on disease progression, found that nutritional impairment was highly prevalent in patients with AD. The authors also pointed out that the identification of the nutritional status in early diagnosis, could help those patients who are at a higher risk of disease progression. 8 The relevance of assessing the nutritional status with different indicators in patients with AD, was also reported in other investigations 9,1011 .
In view of all the findings discussed above, this study investigated nutritional risk factors using the clinical dementia rating (CDR), in patients with Alzheimer's disease (AD).

II. CASES AND METHOD
This study is part of a more comprehensive research project on lifestyle aspects in elderly patients with dementia. Some nutritional aspects have been addressed in another paper 5 . This was a cross-sectional study, which included outpatient elderly individuals (n=43) aged ≥65 years with diagnosis of suspected DA, according to the Diagnostic and Statistical Manual of Mental Disorders 12 , the recommendations of the European Federation of Neurological Societies 13 and the Brazilian Academy of Neurology 14 . Clinical dementia rating (CDR) 15 was used to stage the severity of dementia, that was classified as mild, moderate or severe. Patients with other serious illnesses and patients and/or caregivers unable to answer the evaluation questions were excluded. The study was approved by the institution's ethics research committee (No. 1,234,677) and was started after the guardians signed the free and informed consent form.

Methodological procedures:
a) Nutritional assessment by anthropometry: According to standardized procedures and cutoff points reported in the literature such as the body mass index (BMI) for the elderly 16 , the calf circumference (CC) 17 , the thickness of the adductor pollicis muscle (APM) 18,19 , the handgrip strength (HGS) 20,21,22 and waist circumference 23,24 . The anthropometric indicators of body composition 17,25 of arm circumference (AC), triceps skinfold (TSF), arm muscle circumference (AMC) and sub-scapular skinfold (SSF), were classified in percentile distribution as: lower than the 5 th percentile (<P5: depletion); between the 5 th percentile and below the 10 th percentile (P5¬¬ -<P10: risk of depletion); between 10 th and 90 th percentiles (P10 -P90: normal weight); above the 90th percentile and up to the 95 th percentile (> P90 -P95: risk for excess) and above the 95th percentile (> P95: excess). b) Mini Nutritional Assessment (MNA): The MNA questionnaire was applied and the nutritional status was classified according to the cutoff points established as eutrophic, risk of malnutrition and malnutrition 26 . c) International physical activity questionnaire -short form (IPAQ-SF): Physical activity was assessed according to a standardized and validated instrument for the Brazilian population 27 . For the purpose of analysis, in this study, physical activity was classified as: sedentary or active. d) Statistical analysis: A descriptive analysis was performed with frequency tables for categorical variables and measures of position and dispersion for continuous variables. The Chi-square or Fisher's exact test was used, when necessary; for comparing proportions. To compare continuous or orderable measurements between 2 groups, the Mann-Whitney test was applied and among 3 groups, the Kruskal-Wallis test. Later, to identify the predictors of disease severity by the CDR clinical score, regression models were used, such as univariate and multiple logistic regression analysis. The variable selection process employed was stepwise. The level of significance adopted for the statistical tests was 5%.
There was no statistically significant difference in the relationship between all anthropometric parameters, age and IPAQ-SF with the CDR scores (Table  1). In the analysis among all the anthropometry parameters and physical activity classified by IPAQ, no significant statistical difference was found in all the variables studied ( Table 2). The other anthropometric data were not significantly related to the practice of Physical Activities in AD elderly ( Table 2). When investigating the risk factors associated with the CDR score, using univariate and multiple logistic regression analysis, it was found that in the final model, age (p=0.0481; OR=1.097; 95% CI=1.001; 1,202) and the assessment of nutritional status by MNA (p=0.0159; OR=4,815; 95% CI=1,342; 17,282), were the factors that, together, better discriminated the severity of the disease. Each additional year of age increased by 9.7% the chance of CDR score 2 or 3. The patients' nutritional status by MNA, yielded patients classified as malnourished or at risk of malnutrition with a chance of being a score 2 or 3, 4.8 times higher when compared to the nutritional status of normal weight (Table  3).  26 . And, the present study pointed out MNA (risk of malnutrition and malnutrition), as a predictor of the severity of the disease in elderly people with AD. The pathophysiological mechanisms between nutritional status and AD are not yet fully understood. Our data suggest that older age and risk of malnutrition and malnutrition and nutritional imbalance conditions are associated with greater severity of dementia in elderly people with AD. An association between nutritional status and the rate of cognitive and functional decline was also observed in an observational longitudinal study 11 , using MNA, CDR and the Mini-Mental State Exam. In the study in question, it was found that a worsening of the CDR, during dementia, was associated with lower MNA scores 11 .
Other studies suggest an association between a greater impairment of nutritional status with more advanced AD stages, faster cognitive and functional decline and higher mortality rates 4,8,28 .
Unlike the findings found in this investigation, a prospective study recently carried out in Portugal 29 with elderly patients with AD, showed that malnutrition, unintentional weight loss, low weight, low values of calf circumference and muscle circumference of the arm, of handgrip strength and gait speed, were associated with a higher risk of death, regardless of gender, age, marital status, education and cognitive function status 29 . In our study, among the investigated nutritional variables, only malnutrition was associated with AD. And in a Korean study 7 that investigated the nutritional status and clinical risk factors of malnourished patients, the authors observed that dementia was considered an independent predictor for the risk of malnutrition, further suggesting that cortical thinning in the left temporal regions, could be related to nutritional status. Another recent study with female patients with mild cognitive impairment and early-stage Alzheimer's disease, found malnutrition associated with behavioral and psychiatric symptoms of dementia 30 .
Other recent findings 31 suggest that malnutrition may be related not only to impaired cognition, but also to the pathology of AD. The authors pointed out that AD biomarkers were associated with the MNA score, waist circumference and BMI, and the associations with the MNA score remained after adjustment for cognitive performance 31 .
The present study found no association between the severity of the disease and the HGS. Different data were recently reported in a study with an elderly Japanese population, which showed a greater decline in HGS in the elderly, associated with the late onset of dementia 21 .
As limiting factors of this study, it is highlighted that our service is a university hospital, but not a tertiary public health center in Brazil. This study is crosssectional, with a relatively small sample of cases, although it is a specific population with elderly population with AD, monitored on an outpatient basis. However, we must consider that the hospital and outpatient service, where our study was conducted, is part of a representative clinical and surgical neurology service that includes AD patients care in a large metropolitan region. Thus, the individuals who participated in this study were representative of all those who undergo routine clinical treatment, besides the fact that this population underwent specific screening that allowed diagnostic tracking of the severity of the disease. These points can be considered the strong points of our investigation. Anyway, further investigations with a larger sample size are still need to assess the impact of these findings. We can also suggest that nutritional counseling be offered to those patients who are at risk of malnutrition.

V. CONCLUSION
The findings in this study allowed us to conclude that age and MNA, discriminate the severity of AD and were considered risk factors for the severity of the disease.